The present invention is novel compounds which are indoles substituted at the 3-position with [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene and pharmaceutically acceptable acid addition or base salts thereof, pharmaceutical compositions and methods of use thereof. The invneiton compounds are now found to have activity as inhibitors of one or both of cyclooxygenase and 5-lipoxygenase providing treatment of conditions advantageously affected by such inhibition including inflammation, arthritis, pain, fever, and the like. Thus, the present invention is also a pharmaceutical composition or method of use thereof.
Although indoles are known antiinflammatory agents and various compounds having a [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene] substituent are known as antiinflammatory agents, for example, with 3,5-di-tertizry-butyl-4-hydroxyphenyl groups as disclosed in EP Application No. 89 109406.2 and U.S. patent application Ser. No. 499,937 (incorporated herein by reference) now abandoned, the present combination of ring systems, substituents and moieties differs from those previously known. Other compounds having an indole ring system are shown in copending U.S. application Ser. No. 697,823.
Compounds are disclosed having an indole system substituted at the 2- or 3-position in European Publication Number 279,263 and U.S. Pat. No. 4,464,382.
U.S. Pat. No. 3,161,654 discloses an indole ring system substituted through the nitrogen with p-chlorobenzoacyl.
These compound may be distinguished from the compounds of the invention herein by the unique combination of indole and [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene] substituent disclosed here.
[3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methylene]-1,3-dihydro-2H-i ndole-2-one is disclosed in the Russian journal of "Chemistry of Heterocyclic Compounds," Vol 9, p. 34 (1973) citing Khim Getrotsikl Soedin, V-9, p 40-44 (Russ), 1973, which further suggests that sterically hundred (shielded) phenols are known to have a number of specific chemical and physiochemical properties having applications as disclosed by L. M. Strigun, et al, Usp; Khim, 37, 969 (1968); G. A. Nikiforov and V. V. Ershov, Usp. Khim, 39, 1369 (1970); L. R. Mahoney, Angew; Chem., 81, 555 (1969); N. M. Emanuel, in: Methods for the Synthesis of and Search for Antitumorigenic Preparations [in Russian], Medgiz, Moscow (1962), p 22; and D. Harman, Agents' Actions, 1, 3 (1969).